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Brief Article
Novel Aza-analogous Ergoline Derived Scaffolds as Potent Serotonin 5-HT6 and Dopamine D2 Receptor Ligands. Niels Krogsgaard-Larsen, Anders A. Jensen, Tenna J Schrøder, Claus T Christoffersen, and Jan Kehler J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm5003759 • Publication Date (Web): 30 May 2014 Downloaded from http://pubs.acs.org on June 7, 2014
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Journal of Medicinal Chemistry
Novel Aza-analogous Ergoline Derived Scaffolds as Potent Serotonin 5-HT6 and Dopamine D2 Receptor Ligands. Krogsgaard-Larsen, Nielsa†; Jensen, Anders A.a†; Schrøder, Tenna. J.b; Christoffersen, Claus. T.b; and Kehler, Janb* a
Department of Drug Design and Pharmacology, The Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. bH. Lundbeck A/S, Department of Medicinal Chemistry, 9 Ottiliavej, DK-2500 Valby, Denmark
ABSTRACT: By introducing distal substituents on a tetracyclic scaffold resembling the ergoline structure two series of analogues were achieved exhibiting subnanomolar receptor binding affinities for the dopamine D2 and serotonin 5-HT6 receptor subtype respectively. While the 5-HT6 ligands were antagonists, the D2 ligands displayed intrinsic activities ranging from full agonism to partial agonism with low intrinsic activity. These structures could potentially be interesting for treatment of neurological diseases such as schizophrenia, Parkinson’s disease and cognitive deficits.
Several of the monoaminergic receptors mediating the effects of dopamine, serotonin, and norepinephrine constitute key targets in the current treatment of a wide range of neurological, psychiatric and cognitive disorders. In Parkinson’s disease (PD) a degeneration of dopamine neurons in the basal ganglia, predominantly the substantia nigra pars compacta nuclei, is evident.1 To reduce the symptoms arising from this progressive neurodegeneration, PD is principally treated with L-DOPA or synthetic dopaminergic agonists. However, the severe drawbacks and temporary effectiveness of this treatment urge the development of therapeutic alternatives.2 Schizophrenia (SZ) is a chronic disorder characterized by an array of clinical features resulting in abnormal mental functions and disturbed behaviour.3 The major treatment paradigm in SZ is the use of dopamine D2 receptor antagonists or partial agonists with low intrinsic activity and all current clinical antipsychotics target this receptor.4,5 Finally, the cognitive impairment observed in CNS disorders such as Alzheimers disease (AD) and SZ have in several studies been shown to be addressed by serotonin 5-HT6 receptor antagonists.6-8 R 8
7
NH2
6
N 5
9
4
10 11
12
D
H H
14
H
1N H
D
C
Ergoline scaf f old
A
N
Clavine type Agroclavine (1)
A
N
H
C B N H
O
HO O
O
3 2
13
N
O B N H
Lysergic Acid Amides Ergine (2)
N H
N
D
O
N
H
C A
B N H
Peptide Ergot Alkaloids Ergocornine (3)
Figure 1: The basic ergoline scaffold and examples of the three types of naturally occurring ergot alkaloids (1-3). Ergot alkaloids are derivatives of the tetracyclic ergoline scaffold and can be divided in to three main groups (Figure 1). The
ergot alkaloids display a diverse spectrum of pharmacological properties, including central, peripheral and neurohormonal activities that arise from their activities at various monaminergic receptors.9 Ergot alkaloids are used in the clinical treatment of PD and have also been pursued as putative therapeutics for treatment of SZ.10-13 Thus, the basic ergoline structure presents an intriguing scaffold for further modification and development of novel monoaminergic receptor ligands. In the present study, the potential of a novel ergot analogue scaffold was probed through the design and synthesis of two series of tetracyclic piperazine analogues (15-27 and 29-41). These compounds were pharmacologically characterized at either the dopamine D2 or the serotonin 5-HT2C and 5-HT6 receptors. The objective of this preliminary study was to obtain an ergoline analogous scaffold by combining two privileged scaffolds (indole and phenyl piperazine) that upon introduction of distal substitutions on the resulting tetracyclic core scaffold could embrace the different monoaminergic pharmacophore models and target various monoaminergic receptor subtypes. RESULTS AND DISCUSSION Chemistry. Carbamate-protected piperazino indoles 7 and 8 are readily available from protection of commercially available 4-piperazinoindole, however, the disbursement of the compound prompted an alternative synthetic route. The chemistry leading from 4-bromoindole 1 to compound 12 and 25 followed a previously developed protocol (Scheme 1).14 Tetracycle 15 was readily alkylated or benzylated selectively at the secondary amine. The syntheses of the derivatives 16-27 were only performed in small scale and purified by preparative LC-MS with the n-propyl analogue being the exception for full characterization purposes. Boc-protected tetracycle 28 was sequentially sulphonated at the indole nitrogen and deprotected to complete a small, selected series of phenylsulphone-substituted analogues.
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Scheme 1.a O
O Br
N
Br
a 96 %
N H
N
b
N O O S
79 %
N O O S
4 5
6
O
O
R
N
O
N
O
e N O O S
O
O
R
N
80 % c R
N
N
d
O
11: 92 % 12: 86 %
N
9: 49 % 10: 36 %
N H
9: R = Bn 10: R = t Bu
11: R = Bn 12: R = t Bu
O
N H
7: R = Bn 8: R = t Bu
13: 55 %
f 14: 51 % O
O
R H N
N
g
N
R N
h
N
60 % N O S O
Preperative library
N H
N H
15
16: R = Me 17: R = Et 18: R = n Pr 19: R = n Bu 20: R = i Bu 21: R = n Pn 22: R = i Pn - 23: R = CH2 c Hex 24: R = Bn 25: R = 2 CH2 biPh 26: R = 3 CH2 biPh 27: R = 4 CH2 biPh
13: R = Bn 14: R = t Bu
c
76 % O
H N
O N
N
i -
N
64 87 % N H
N
N O S
O
R
28 29: R = H 30: R = 2 Me 31: R = 3 Me 32: R = 4 Me 33: R = 2 F 34: R = 3 F 35: R = 4 F
36: R = 2 Cl 37: R = 3 Cl 38: R = 4 Cl 39: R = 2 OMe 40: R = 3 OMe 41: R = 4 OMe
a
Reagents and conditions: (a) p-TsCl, n-Bu4NHSO4, NaOH (16 %), PhMe, 60 °C, 2 h; (b) Cbz-piperazine, Pd(dba)2, 1-biphenyl-P(t-Bu)2, NaO-t-Bu, PhMe, reflux, 15 h; (c) Mg (dust), MeOH (dry), THF (dry), sonication, rt, 30 min; (d) 1) POCl3, DMF, 0 °C, 1.5 h - rt, 2 h; 2) H2O, rt, 45 min; (e) p-TsCl, n-Bu4NHSO4, NaOH (16 %), PhMe, rt, 45 min; (f) 1) p-TsNHNH2, PhMe, sonication, rt, 3 h, 2) NaH (60 % in mineral oil), PhMe, microwave irradiation, 130 °C, 12 min; (g) KOH (20 % in H2O), DMSO, microwave irradiation, 150 °C, 4 min. (h) DIPEA, DMSO, alkyl bromide, 60 °C, 42 h (16 - 23); DIPEA, DMSO, benzyl bromide, rt, 18 h (24 - 27); (i) 1) pTsCl, n-Bu4NHSO4, NaOH 16 %), PhMe, rt, 2 h; 2) MeOH, Et2O, 2 M HCl in Et2O, rt, 18 h.
substituent.15 Thus, it was decided to include small straight or branched alkyl substituents up to the length of the pentyl chain in the analogues. Moreover, the dopamine D2 affinity of bifeprunox (43) indicates a very efficient interaction between the receptor and the aromatic biphenyl group of the ligand.16 Due to the size of the N-substituent it will have to protrude into a different and much more spacious cavity of the binding site as it is seen in the case of bromocriptine (44).17 In view of this, analogues with benzyl or different methylene biphenyl substituents in this position were also included in this series. In the evaluation of the pharmacological properties of the synthesized analogues described vide infra, it is important to keep in mind that the compounds were tested as racemic mixtures and that the conclusions concerning the spacious cavity is based on the crystal structure of 5-HT1B co-crystallised with ergotamine as a model for the D2 receptor binding site, which is in correlation with existing literature.17-19 As can be seen from Table 1, a pronounced correlation ranging over more than a 1000 fold difference in binding affinities exists between the size of the substituent and the binding affinities of the compounds at the human D2L receptor. Interestingly, the n-Pr analogue 18 displays relatively low binding affinity, which could indicate that the alkyl substituent in this position is not able to accommodate the restriction of the alkyl binding cavity and therefore will have protrude the larger cavity of the binding site.15 The spacious orientation of the biphenyl moiety also seems to be of great importance despite protruding into a different and much larger cavity of the D2 receptor pocket, resulting in a 700-fold difference in D2 binding affinity.17 Compound 26 stands out as the most potent D2 receptor ligand to come from the series displaying an interesting D2 receptor profile compared to the structurally related compounds pergolide (42), bifeprunox (43), bromocriptine (44), and lisuride (45).16,20-22 The binding affinity of compound 26 was comparable to that of lisuride (45), the classical anti-parkinson ergot, while the compound exhibited a significantly higher D2 affinity than pergolide (42) and bromocriptine (44) also used in the treatment of PD.18 However, being a partial D2 agonist with an intrinsic activity comparable to that of bifeprunox (43), compound 26 resembles a potential antipsychotic more than an anti-Parkinson therapeutic by shifting the D2 profile towards those of typical antipsychotics such as chlorpromazine (46) and haloperidol (47), which display antagonism and inverse agonism at the D2 receptor, respectively (Figure 2).23 Interestingly, an inverse correlation between the dopamine D2 efficacy and the size of the amine substituent can be observed for the compounds in this series characterized functionally. Thus, compounds 22 and 23 which comprise smaller alkyl substituents are full agonists of the D2 receptor and could be speculated to hold more potential as putative PD therapeutics than compound 26. Cl
N
HO O N
N
Pharmacology. Naturally occurring ergot structures are almost exclusively methylated at the amine in the 6-position. However, different small alkyl substituents are accommodated by dopamine agonists such as 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP) and pergolide (42), which is most likely due to a welldefined pocket in the monoamine receptor fitting the n-propyl
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HO
OH
Cl HO
S
Chlorpromazine (46)
F
NH2
O
Haloperidol (47)
L DOPA (48)
Figure 2: The chemical structures of chlorpromazine (46), haloperidol (47) and L-DOPA (48).
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A pronounced consequence of neurodegenerative diseases such as AD and SZ is cognitive dysfunction.6,7 Due to its CNS distribution and its ability to modulate multiple neurotransmitter systems involved in cognition, the serotonin 5-HT6 receptor has emerged as an interesting target through which this core feature of AD and SZ can be addressed.6-8 The serotonin 5-HT2C Table 1. Dopamine hD2L receptor binding affinities and functional efficacies of compounds 15 – 27 in comparison to benchmark compounds such as pergolide (42), bifeprunox (43), bromocriptine (44), and lisuride (45). R
S
N
N
N
H
N
N
H
O N H
15 27
N H
Bif eprunox (43)
Pergolide (42) O
HO
H N
O
O N
O
N H
N H
N
N
H
N
N
O
O
Br
N H
N H
Bromocriptine (44)
No.
H
Name (42-45) R (15-27)
Lisuride (45) hD2L
Ki (nM)
pKi ± S.E.M.
Emax
b
52
42
Pergolide
26
7.59 ± 0.06
43
Bifeprunox
2.3
8.64 ± 0.02b
27
b
28
44
Bromocriptine
15
7.83 ± 0.08
45
Lisuride
0.66
9.18 ± 0.04b
21
2100
5.68 ± 0.05
a
n.t.
a
n.t.
15
H
16
Me
660
6.18 ± 0.02
17
Et
140
6.85 ± 0.05a
n.t.
a
n.t.
18
n-Pr
570
6.24 ± 0.01
19
n-Bu
110
6.96 ± 0.02a
n.t.
a
n.t.
20
i-Bu
310
6.51 ± 0.05
21
n-Pn
98
7.01 ± 0.13a
n.t.
a
96 95
22
i-Pn
24
7.62 ± 0.04
23
CH2-c-hex
54
7.27 ± 0.13a a
51 n.t.
24
Bn
130
6.89 ± 0.06
25
2-CH2-biPh
450
6.70 ± 0.11b
26
3-CH2-biPh
0.65
9.64 ± 0.06a
35
27
4-CH2-biPh
140
6.92 ± 0.05a
n.t.
Dopamine D2 affinity: Displacement of specific [3H]-raclopride binding to membranes of CHO-K1a-hD2L cells (15-27), Displacement of specific [125I]iodosulpride at recombinant, human dopamine receptors in CHO cells (42, 44, 45).20 Displacement of specific [3H]nemonapride at dopamine D2 transfected COS-7 cells (43).16 Dopamine D2 efficacy: [125I]-cAMP in CHO cells (22-24,26). [35S]GTPγS binding to hD2-like receptors expressed by CHO cells (42, 44, 45).21 [35S]-GTPγS binding to membranes of Sf9 cells (43).22 n.t. = not tested, a(n = 2), b(n = 3).
receptor subtype has also been identified as a potential pharmacological target in relations to cognitive deficits and SZ.4,24,25 While both receptor subtypes have been included in this preliminary study focus will vide infra be upon the pharmacological interactions of the tetracyclic derivatives and the 5-HT6 receptor. In order to introduce 5-HT6 receptor activity in the tetracyclic ergot analogous scaffold, a phenylsulphonylate substituent was introduced at the indole nitrogen of compound 15, as this would address the receptor interacting elements defined in the classical 5-HT6 pharmacophore model.6,26 A small selection of substituents with a limited size and different electronical properties were introduced into this series of compounds in order to probe their potential as 5-HT6 ligands.6,27 As can be seen from the 5-HT6 receptor binding affinities exhibited by the sulphonamide analogues outlined in Table 2, substituents in the 4-position of the scaffold appear to be unfavorable compared to substituents in the 2- and 3-positions, whereas the receptor does not seem to discriminate between the latter two positions. It is not possible to derive any SAR conclusions about the size and electronic properties of the substituents chosen except that introduction of fluorine in these positions seem to be favored by the receptor. Compound 34 displayed the highest binding affinity (0.75 nM) at the 5-HT6 receptor and a 250-fold selectivity for this receptor over the 5-HT2C receptor. Moreover, the compound was found to be an antagonist at the 5-HT6 receptor (CEREP).28 While the subnanomolar 5-HT6 binding affinity displayed by compound 34 was lower than that exhibited by the structurally similar 5-HT6 antagonist SB-742457 (49), it was either higher or comparable to those exhibited by other sulphonyl-containing compounds such as Ro 63-0563 (50) and SB-271046 (51) and also by LU AE58054 (52).29,30 Interestingly, despite distinct structural differences these three compounds display similar 5HT6/5-HT2C binding selectivity ratios as compound 34. Mesulergine (53), which also contains the ergot scaffold, but with the sulphonamide attached to the piperidine moiety, displays the opposite 5-HT6/5-HT2C selectivity. Preliminary clearance and metabolic studies for compound 26 (3.9 L/kg/h(human)) indicated that it would be both metabolized and excreted at a rate unsuitable for a drug. In contrast, compound 34 (0.8 L/kg/h (human)) displayed a more favorable profile in a potential therapeutic context (1.3 L/kg/h (human)). The fast metabolism of compound 26 was not unexpected, since biphenyl moieties are known to be promptly metabolized by 4-hydroxylation.31 Thus, it is possible that the metabolic and clearance profile of these biphenylic analogues could be improved by introducing a substituent in the 4 position, thereby preventing this elaborate 4-hydroxylation. Interestingly, introduction of small substituents in the 4-position of biphenyl substituted 4-piperazineindole analogues have been found to increase the D2 receptor binding affinity (data not shown), which suggests that the problematic clearance and metabolism properties of this scaffold could be addressed without compromising the pharmacological properties of the compounds. In the present study the pharmacological properties of the two series of compounds were characterized on selected monoaminergic receptor subtypes that are well established as potential therapeutic targets in relations to PD, SZ and cognitive dysfunction.1-8 Considering the rich pharmacology of ergot
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structures, it will be important to characterize the pharmacological properties of these compounds at additional monoaminerTable 2. Serotonin 5-HT6 and 5-HT2C receptor binding affinities of compounds 29-41 in comparison to the benchmark compounds 49-53. H N
H N NH
N
HN
N N N O
N O S
S
2
O
HN
O
S NH2
R 4
SB 742457 (49)
H N Cl
Ro 63 0563 (50)
F F
F
O
O
F
NH
N
N
S
O
N
O
H
S
S
NH
O
N
F
SB 271046 (51)
No.
H N
H
O N H
Mesulergine (53)
LU AE58054 (52)
Name (49-53)
h5-HT2C
h5-HT6
R (29-41)
Ki (nM)
pKi ± S.E.M.
Ki (nM)
pKi ± S.E.M.
49
SB-742457
-
-
0.17
9.78 ± 0.14d
50
Ro 63-0563
2042
5.69 ± 0.01e
12
7.91 ± 0.02b
3
8.52 ± 0.09a
51
SB-271046
770
6.11 ± 0.15
a c
c
52
LU AE58054
250
6.60 ± 0.04
0.83
9.08 ± 0.06
53
Mesulergine
1.82
8.74 ± 0.03b
776
6.11 ± 0.12e
29
H
280
6.55 ± 0.01
9
8.05 ± 0.04a
30
2-Me
470
6.33 ± 0.06
21
7.68 ± 0.05c
31
3-Me
460
6.34 ± 0.04
24
7.62 ± 0.04a
32
4-Me
780
6.11 ± 0.03
96
7.02 ± 0.12c
33
2-F
350
6.46 ± 0.02
n.t.
n.t.
34
3-F
240
6.62 ± 0.07
0.75
9.12 ± 0.04a
35
4-F
1100
5.96 ± 0.01
29
7.54 ± 0.10c
36
2-Cl
460
6.34 ± 0.06
n.t.
n.t.
37
3-Cl
340
6.47 ± 0.07
47
7.33 ± 0.10c
38
4-Cl
1200
5.92 ± 0.03
184
6.74 ± 0.14c
39
2-OMe
870
6.06 ± 0.04
26
7.59 ± 0.07c
40
3-OMe
370
6.43 ± 0.03
24
7.62 ± 0.34c
41
4-OMe
2900
gic receptors such as 5-HT2A (hallucinogenic properties) and 5HT2B (inadvertent heart effects), just to mention a few, in the future.37 Embracing the complexity of neurological disorders accentuate the need of therapeutics to display a distinct pharmacological profile rather than being receptor subtype selective. In relation to the pronounced conservation of the orthosteric binding sites in the monoaminergic receptors it would also be interesting to merge the D2 and 5-HT6 phamacophores and implement the tetracyclic structure in a hybrid scaffold, since the combination of either D2 receptor agonism or antagonism with 5-HT6 antagonism could hold great therapeutic potential.
O
O 3
29 41
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5.54 ± 0.07
168
c
6.77 ± 0.14
Serotonin 5-HT2C affinity: Displacement of specific [3H]mesulergine binding to human 5-HT2C receptors in membranes of tsA-201 cells (29-41), displacement of specific [3H]5HT at human recombinant 3T3 cells (50),32 displacement of specific [3H]5-HT binding to membranes of AV12 cells (51, 52),33 displacement of specific [3H]5-HT at human recombinant HEK-293 cells (53),34 Serotonin 5-HT6 affinity: Displacement of specific [3H]LSD binding to membranes of BHK-h5HT6 cells (29-41, 51, 52),33 Displacement of specific [3H]LSD binding to membranes of Hela cells (49, 50, 53).32,35,36 n.t. = not tested, a(n = 2), b(n = 3), c(n = 4), d(n = 10), e(n = multiple).
CONCLUSION The present study has identified a novel, pharmacologically interesting and both metabolically and chemically stable scaffold that by distal substitutions potentially can address either the dopaminergic deficits in PD patients or the cognitive impairments of disorders such as SZ and AD. However, despite the intriguing pharmacological properties of the analogues in these series compared to existing tool compounds and compounds in clinical trials or on the market, further pharmacological profiling of these compounds is required in order to evaluate their therapeutic potential. In particular, it will be important to characterize the functional properties of the compounds at other monoaminergic receptors than the D2, 5-HT6 and 5-HT2c receptors in this study. Furthermore, it will be interesting to isolate the enantiomers of selected analogs and subjected these to detailed pharmacologically characterization. EXPERIMENTAL SECTION Purification performed using prepacked ISOLUTE IST flash columns, ISOLUTE SCX cation exchange columns or preparative LC-MS (See supporting information). All final compounds displayed a purity of ≥95 % (ELS). General procedure for alkylating compound 15 (16-23): Tetracyclic compound 15 (15 mg, 0.07 mmol, 1.00 eq) was dissolved in DMSO (2 mL) and added DIPEA (20 μL, 0.11 mmol, 1.64 eq.) and alkyl bromide (1.6 eq.). The mixture was heated to 60 °C and stirred over night in a sealed vial under argon. Additional alkyl bromide (0.8 eq.) was added and reaction mixture stirred at 60 °C for 24 h. The mixtures was purified through a SCX cation-exchange column, concentrated in vacuo on a centrifuge, dissolved in 180 μL DMSO and purified using preparative LC-MS. General procedure for benzylating compound 15 (24-27): Tetracyclic compound 15 (15 mg, 0.07 mmol, 1.00 eq) was dissolved in DMSO (2 mL) and added DIPEA (20 μL, 0.11 mmol, 1.64 eq.) and benzyl bromide (1.6 eq.). The reaction mixture was stirred over night at room temperature. The mixtures was purified through a SCX cation-exchange column, concentrated in vacuo on a centrifuge, dissolved in 180 μL DMSO and purified using preparative LC-MS. General procedure for sulphonation and deprotection of compound 28 (29-31 and 33-41): Boc-protected tetracyclic compound 28 (75 mg, 0.24 mmol, 1.00 eq) was weight out in a 4 mL vial, added toluene (1.2 mL) and tetrabutylammonium hydrogensulfate (8 mg, 0.02 mmol, 0.10 eq). The substituted benzenesulfonyl chloride (1.25 eq) and 16 % NaOH (1 mL) was
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added sequentially. The vial was sealed and the mixture was stirred vigorously at room temperature for 2 – 3 h. The organic phase was isolated and the aqueous phase was reextracted with toluene (2 x 2 mL). The organic phases were combined, washed with brine (2 mL), dried over MgSO4, filtered, concentrated in vacuo and purified by flash chromatography to yield a clear oil. The oil was dissolved in Et2O (1.5 mL) and MeOH (1.5 mL) before 2M HCl in Et2O (1.5 mL) was added. The mixture was stirred at room temperature for 24 h under argon. The mixture was concentrated in vacuo, dissolved in water (8 mL), added 2M NaOH (2 mL) and EtOAc (10 mL). After thorough mixing the mixture was filtered, the organic phase isolated and the aqueous phase reextracted with EtOAc (10 mL). The combined organic phases was washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. ASSOCIATED CONTENT Supporting information Experimental procedures and full characterization of all new compounds including 1H NMR and 13C NMR spectre and pharmacological methods. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION † Authors have contributed equally to this article. Corresponding Author *Phone: +45 36 43 32 32. E-mail:
[email protected]. Notes The Authors declare no competing financial interest ACKNOWLEDGEMENT The chemistry described was conducted at H. Lundbeck A/S. We gratefully acknowledge the research facilities and materials provided by H. Lundbeck A/S and Department of Drug Design and Pharmacology, The Faculty of Health and Medical Sciences, The University of Copenhagen. Niels Krogsgaard-Larsen was supported by a DRA PhD scholarship provided by the Faculty of Health and Medical Sciences, The University of Copenhagen in collaboration with H. Lundbeck A/S. Anders A. Jensen was supported by the Novo Nordisk Foundation and the Aase and Ejnar Danielsen Foundation. The cDNA of the human 5-HT2C receptor was a kind gift from Drs. Alan Saltzman and Stuart Sealfon.
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TABLE OF CONTENTS GRAPHIC
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Dopamine D2 agonist Potential Parkinson's disease therapeutic H N H N
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Serotonin 5 HT6 antagonist a o en co P t ti l gnitive enhancer
Ergoline analogue
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Dopamine D2 partial agonist Potential antipsychotic therapeutic
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